12-2634330-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000719.7(CACNA1C):c.3862G>T(p.Ala1288Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000139 in 1,581,328 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1288T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 9.81

Publications

8 publications found

Variant links:

Genes affected

CACNA1C (HGNC:1390): (calcium voltage-gated channel subunit alpha1 C) This gene encodes an alpha-1 subunit of a voltage-dependent calcium channel. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization. The alpha-1 subunit consists of 24 transmembrane segments and forms the pore through which ions pass into the cell. The calcium channel consists of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. There are multiple isoforms of each of these proteins, either encoded by different genes or the result of alternative splicing of transcripts. The protein encoded by this gene binds to and is inhibited by dihydropyridine. Alternative splicing results in many transcript variants encoding different proteins. Some of the predicted proteins may not produce functional ion channel subunits. [provided by RefSeq, Oct 2012]

CACNA1C Gene-Disease associations (from GenCC):

Timothy syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
long QT syndrome
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
long QT syndrome 8
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
Brugada syndrome
Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, ClinGen
Brugada syndrome 3
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
intellectual disability
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
short QT syndrome
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, ClinGen

CACNA1C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.3862G>T	p.Ala1288Ser	missense_variant	Exon 30 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.3912+618G>T		intron_variant	Intron 30 of 46	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399655.6 link	c.3862G>T	p.Ala1288Ser	missense_variant	Exon 30 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.4096G>T	p.Ala1366Ser	missense_variant	Exon 32 of 50			ENSP00000507184.1
CACNA1C	ENST00000399634.6 link	c.3862G>T	p.Ala1288Ser	missense_variant	Exon 30 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000347598.9 link	c.4006G>T	p.Ala1336Ser	missense_variant	Exon 32 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.3862G>T	p.Ala1288Ser	missense_variant	Exon 30 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.3862G>T	p.Ala1288Ser	missense_variant	Exon 30 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000683781.1 link	c.3952G>T	p.Ala1318Ser	missense_variant	Exon 30 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.3952G>T	p.Ala1318Ser	missense_variant	Exon 30 of 47			ENSP00000507612.1
CACNA1C	ENST00000399638.5 link	c.3946G>T	p.Ala1316Ser	missense_variant	Exon 31 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.3937G>T	p.Ala1313Ser	missense_variant	Exon 31 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.3922G>T	p.Ala1308Ser	missense_variant	Exon 31 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.3862G>T	p.Ala1288Ser	missense_variant	Exon 30 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.3862G>T	p.Ala1288Ser	missense_variant	Exon 30 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000399629.5 link	c.3946G>T	p.Ala1316Ser	missense_variant	Exon 31 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000399591.5 link	c.3862G>T	p.Ala1288Ser	missense_variant	Exon 30 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.3862G>T	p.Ala1288Ser	missense_variant	Exon 30 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.3862G>T	p.Ala1288Ser	missense_variant	Exon 30 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399601.5 link	c.3862G>T	p.Ala1288Ser	missense_variant	Exon 30 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.3862G>T	p.Ala1288Ser	missense_variant	Exon 30 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000682686.1 link	c.3862G>T	p.Ala1288Ser	missense_variant	Exon 30 of 46			ENSP00000507309.1
CACNA1C	ENST00000399603.6 link	c.3912+618G>T		intron_variant	Intron 30 of 46	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000406454.8 link	c.3912+618G>T		intron_variant	Intron 30 of 47	5		ENSP00000385896.3
CACNA1C	ENST00000683824.1 link	c.4077+618G>T		intron_variant	Intron 31 of 47			ENSP00000507867.1
CACNA1C	ENST00000399617.6 link	c.3912+618G>T		intron_variant	Intron 30 of 47	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.4002+618G>T		intron_variant	Intron 30 of 46			ENSP00000507105.1
CACNA1C	ENST00000683956.1 link	c.4002+618G>T		intron_variant	Intron 30 of 46			ENSP00000506882.1
CACNA1C	ENST00000402845.7 link	c.3912+618G>T		intron_variant	Intron 30 of 46	1		ENSP00000385724.3
CACNA1C	ENST00000682336.1 link	c.3987+618G>T		intron_variant	Intron 31 of 46			ENSP00000507898.1
CACNA1C	ENST00000399597.5 link	c.3912+618G>T		intron_variant	Intron 30 of 46	1		ENSP00000382506.1
CACNA1C	ENST00000399644.5 link	c.3912+618G>T		intron_variant	Intron 30 of 46	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.3912+618G>T		intron_variant	Intron 30 of 46			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.3903+618G>T		intron_variant	Intron 30 of 46			ENSP00000507169.1

Frequencies

GnomAD3 genomes

AF:

0.00000663

AC:

AN:

150724

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000144

AC:

AN:

207986

AF XY:

0.0000180

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000334

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000147

AC:

AN:

1430604

Hom.:

Cov.:

AF XY:

0.0000113

AC XY:

AN XY:

708660

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33038

American (AMR)

AF:

0.00

AC:

AN:

40836

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25626

East Asian (EAS)

AF:

0.00

AC:

AN:

38844

South Asian (SAS)

AF:

0.00

AC:

AN:

81558

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51650

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.0000192

AC:

AN:

1094064

Other (OTH)

AF:

0.00

AC:

AN:

59252

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.415

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000663

AC:

AN:

150724

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73486

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40938

American (AMR)

AF:

0.00

AC:

AN:

15072

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5104

South Asian (SAS)

AF:

0.00

AC:

AN:

4772

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10200

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67874

Other (OTH)

AF:

0.00

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.00000830

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome

Uncertain:1

Sep 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1288 of the CACNA1C protein (p.Ala1288Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 1735622). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CACNA1C protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Cardiovascular phenotype

Uncertain:1

Feb 14, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.A1288S variant (also known as c.3862G>T), located in coding exon 30 of the CACNA1C gene, results from a G to T substitution at nucleotide position 3862. The alanine at codon 1288 is replaced by serine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, the association of this alteration with CACNA1C-related neurodevelopmental disorder is unknown; however, the association of this alteration with Timothy syndrome or long QT syndrome is unlikely.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

CardioboostArm

Benign

0.030

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.18

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.43

T;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.0

.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

M_CAP

Pathogenic

0.43

MetaRNN

Uncertain

0.43

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

0.0

.;.;.;.;.;.;.;.;N;.;.;.;.;.;.;.

PhyloP100

9.8

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-1.3

N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N

REVEL

Uncertain

0.56

Sift

Benign

0.23

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.095

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

Vest4

0.67

ClinPred

0.35

GERP RS

5.5

gMVP

0.94

Mutation Taster

=44/56

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over